Aging is a major risk factor for the development of type 2 diabetes (T2DM). Approximately 50% of subjects aged ≥65 have diabetes or impaired glucose tolerance, a pre-diabetic state. Skeletal muscle is the main site of insulin-stimulated glucose disposal and aging is characterized by muscle insulin resistance. It has been suggested that the insulin resistance of aging results from an age-related accumulation of intramyocellular lipids which impair insulin action. However, the molecular basis for the accumulation of intramyocellular fat and insulin resistance in the elderly remains unknown. AMP-activated protein kinase (AMPK) is an energy-sensing enzyme whose activation results in increased fatty acid oxidation. Purpose: In the proposed study, we will test the hypotheses that the decrease in fat oxidation that occurs in muscle from older human subjects is secondary to an age-mediated reduction in AMPK signaling, in vivo, and that upregulating AMPK signaling through exercise training will result in (and correlate with) increased fat oxidation, reduced intramyocellular lipids, and improved insulin action. Using a primary human muscle cell culture system, also we will test that hypotheses that reduced AMPK signaling in old myotubes leads to lower fat oxidation (in vitro) and that chemical activation of AMPK in old myotubes to the same level as young muscle cells will restore insulin action and help prevent fat-induced insulin resistance. To test these hypotheses the following specific aims (objectives) are proposed: